Global search for stable conformations of amyloid-β dimer in water by replica exchange MD and ab initio fragment MO calculations

Abstract

Amyloid-β peptides (Aβs) play a key role in pathogenesis of Alzheimer's disease. Since the aggregation of Aβs is involved in the pathogenesis, the conformations of Aβ aggregates have been investigated by many experimental and computational studies. In the present study, we performed replica exchange molecular dynamics (REMD) calculations to obtain various conformations of full-length Aβ(1--42) dimer in water and determined the most stable conformation of the solvated Aβ dimer by ab initio fragment molecular orbital (FMO) calculations. In the most stable conformation elucidated by the present study, β-hairpin and zipper-like β-sheet structure are formed, being consistent with the previous studies. We furthermore investigated the specific interactions between Aβ monomers by FMO calculations, in order to elucidate which residues contribute mainly to the stability of the Aβ dimer. As the result, it is elucidated that Lys16 and negatively charged residues of N-terminal contribute mainly to the stability of the most stable conformation of solvated Aβ dimer. In addition, the present study molecular simulations with solvating water molecules considered explicitly elucidated that some solvating water molecules contribute significantly to the stability of the solvated Aβ dimer.